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Research & Innovation

How Depression Affects the Brain

June 17, 2021

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When we think about depression, what comes to mind are feelings and emotions – or, for some, the absence of feelings and emotions. In order to really understand depression, however, it’s important to be aware that the condition has physical aspects as well. Most people understand what depression looks like on the outside, in terms of a person’s behavior, but our medical understanding of the actual progression of the disease and its treatments continues to evolve.  

What we know right now is that, on a chemical level, depression involves neurotransmitters, which can be thought of as the messengers that carry signals between brain cells, or neurons.  

“The current standard of care for the treatment of depression is based on what we call the ‘monoamine deficiency hypothesis,’ essentially presuming that one of three neurotransmitters in the brain is deficient or underactive,” says Rachel Katz, MD, a Yale Assistant Professor of Clinical Psychiatry.  

But according to Dr. Katz, this is only part of the story. There are about 100 types of neurotransmitters overall, and billions of connections between neurons in each person’s brain.  

There remains much to learn.

A long road to understanding depression

For years and years, doctors and researchers assumed that depression stemmed from an abnormality within these neurotransmitters, particularly serotonin or norepinephrine. But over time, these two neurotransmitters did not seem to account for the symptoms associated with major depression. As a result, doctors began to look elsewhere.  

The search proved fruitful.  “There are chemical messengers, which include glutamate and GABA, between the nerve cells in the higher centers of the brain involved in regulating mood and emotion,”  says John Krystal, MD, chair of Yale’s Department of Psychiatry, noting that these may be alternative causes for the symptoms of depression. 

These two are the brain’s most common neurotransmitters. They regulate how the brain changes and develops over a lifetime. When a person experiences chronic stress and anxiety, some of these connections between nerve cells break apart. As a result, communication between the affected cells becomes “noisy,” according to Dr. Krystal. And it’s this noise, along with the overall loss of connections, that many believe contribute to the biology of depression.  

This “neurobiology of depression” is important to understand. First, it helps doctors understand how the disease develops and evolves. Also important, though, is that those same doctors can then use their new understanding of depression’s mechanisms to build targeted treatment plans. And, since depression is often a long-term disease, people needs long-term treatments for it.  

“There are clear differences between a healthy brain and a depressed brain,” Dr. Katz says. “And the exciting thing is, when you treat that depression effectively, the brain goes back to looking like a healthy brain.”  

We have entered a new era of psychiatry, Dr. Katz adds. As we shift away from a single hypothesis about what causes depression, we are also learning more about the brain as a whole, in all of its complexities.  

In this video, Drs. Katz and Krystal explain how depression affects the brain.